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Idiopathic pulmonary fibrosis 2013 - an update

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Jafar Ahmed

on 11 October 2013

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Transcript of Idiopathic pulmonary fibrosis 2013 - an update

"IPF in 2013 - an update"
Jafar Ahmed
Chapman team , Waitakere hospital
Mr. RA
Tib / fib fracture
Cholecystectomy - "fibrotic" GB
Temazepam, Analgesia
April 2012...
2 months of dizziness (pre-syncopal) and falls
Echocardiogram - SAM and moderate to severe LV tract outflow obstruction
MRI - Significant LV hypertrophy - apical, small LV cavity, dynamic LVOT obstruction, peak gradient >100 mg, extensive intramural fibrosis
Normal angio
ETT - marked BP drop with symptoms at 2 mins
Surgical myomectomy Nov 2012

Feb 2013...
Routine post op Cardiology clinic
No syncope but progressive SOBOE
Plan - Echo , ETT as OP

Repeat Echo March 2013 - moderate to severe basal hypertrophy but no flow obstruction,mild diastolic dysfunction, RV mildly dilated but normal systolic function, pulmonary pressures probably elevated PASP 32

June 2013...
Referred from ETT with biventricular failure
Exercise tolerance <5 m
Exam consistent - Sats 92%OA, JVP up, peripheral oedema, bibasal inspiratory crackles
CXR - increased interstitial markings
Diuresed 3-4 kg
Repeat Echo - LV looked the same , moderate RV dilatation
August 2013...
Very hypoxic on air - 80%
Exam suggestive of biventricular failure
CXR - cardiomegaly and diffuse interstitial changes
No progress on IV diuretics
Repeat Echo - LV much the same , RV severely dilated, moderate - severe RVH , severe RV dysfunction, severe pulmonary HTN

Frusemide infusion
Repeat CXR
"There is persistent fine increase
and interstitial markings bilaterally. This may represent
interstitial oedema however there is no definite peribronchial
cuffing or pleural effusions and this would therefore be atypical.
Diffuse interstitial lung disease could produce this appearance "
"The pattern is most in keeping with UIP"
Discharged with palliative home O2
US data

Mean age = 66 yrs

Exclude known causes of ILD
Old ATS/ERS criteria superseded
New diagnostic criteria
UIP pattern on HRCT (without surgical lung biopsy)
Combination of pattern of HRCT and lung biopsy findings
HRCT pattern in UIP
Histological pattern in UIP
HRCT pattern
Honey combing
Reticular changes
Traction bronchiectasis
Radiology more important than biopsy
Role of lung biopsy
Atypical - less than 50 yrs, rapidly changing, fevers, weight loss, haemoptysis, unexplained extrapulmonary symptoms
Neoplastic (lymphangitis) or infective (TB) process
Potentially treatable (IPF vs HSP) and predict response to treatment
Rarely to diagnose ILD when other tests negative
Best if small amount of tissue required or centrilobular samples

Sarcoid, HSP, infections

Will miss patchy disease - particularly idiopathic
No biopsy when HRCT and clinical picture fit - BIOPSY never changes diagnosis
VATS or open

High diagnostic yield but higher risks

Mortality and morbidity
Surgical biopsy
Role of BAL
Haemoptysis and interstitial picture
haemorrhage, infection, malignancy
Chronic (Hx and radiology)
Sarcoid, HSP, PLAH, infection
Prognosis / Natural History
Mortality 10% annum
Rate of decline of FVC 10-20 x normal (c/w 10 ml/yr)
Mortality risk score
"Conclusions: The 6MWT is a reliable, valid, and responsive measure of disease status and a valid endpoint for clinical trials in IPF"
Exercise tolerance and rate of decline in FVC most important prognostic factors
Aberrant wound healing model - role of the fibroblast
"Unclear if inflammation (resolving prior to presentation) is inciting stimulus or whether aberrant epithelial cells and fibroblastic response to non-specific injury causes fibrosis in absence of inflammation"
Multiple microinjuries to alveolar epithelial cells (fibrotic environment)
Growth factors by injured epithelial cells activate and recruit fibroblasts
fibroblasts and myofibroblasts organise into fibrotic foci (this precedes end-stage fibrosis)
Excess collagen is laid down
Historical approach
Thought to be inflammatory so potent immunosuppressants used

Azathioprine + prednisone
Cyclophosphamide +/- prednisone

marginal or no difference
High dose NAC added to 'standard' therapy Pred + AZA for 1 year
155 patients but 30% lost to follow-up
"CONCLUSIONS - Therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and DLCO in patients with idiopathic pulmonary fibrosis better than does standard therapy alone"

NO true placebo group - NAC possibly ameliorating myeloablative effects of therapy
Panther IPF trial to look at 'triple therapy'
3 arms - triple therapy, NAC alone, placebo
Triple therapy arm stopped early when 50% data collected

Conclusions Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients.
Capacity - 2 trials
Study 1: 435 patients in 3 arms
High dose/ low dose / placebo
Study 2: 344 patients in 2 arms
High dose vs placebo
Cochrane review - "non-steroid agents"
Summary : Reduces the risk of progression by ~ 30%
Anti-fibrotic and anti-inflammatory
Reduces fibroblast profileration
Inhibits TGF and collagen production
Approved in Europe, Canada and Japan
Not approved by FDA (wants more clinical trials) and draft NICE guidelines express reservations about generalisability of trial results and cost effectiveness
Other treatments disappointing
biological response modulators
Clinical trials.gov
Supportive measures
Supplemental O2
Palliative care
Early referral for transplantation (if appropriate)
Thank you
Pros / Cons
only drug with some evidence in a disease with limited evidence base
FVC as a marker of disease progression is a robust end-popint
costs not as high compared with others and can be accommodated by selecting patients who respond and prescribing based on generic guidelines
Small increments in benefit have revolutionalised treatment (oncology) compared with paradigm shifts

Highly select group in clinical trials
Uncertain clinical significance of the observed FVC changes
Skin, GI adverse effects
No improvement in resp symptoms or QOL
No mortality benefit
Cost of perfenidone
Cost effectiveness has not been assessed
Full transcript